期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 19, 期 12, 页码 3253-3258出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2009.04.093
关键词
PYK2; FAK; Kinase; Osteoporosis; hERG; Sulfoximine
The synthesis, in vitro properties, and in vivo pharmacokinetics for a series of sulfoximine-substituted trifluoromethylpyrimidines as inhibitors of proline-rich tyrosine kinase, a target for the possible treatment of osteoporosis, are described. These compounds were prepared as surrogates of the corresponding sulfone compound 1. Sulfone 1 was an attractive PYK2 lead compound; however, subsequent studies determined this compound possessed high dofetilide binding, which is an early indicator of cardiovascular safety. Surprisingly, the corresponding sulfoximine analogs displayed significantly lower dofetilide binding, which, for N-methylsulfoximine (S)-14a, translated to lower activity in a patch clamp hERG K+ ion channel screen. In addition, compound (S)-14a shows good oral exposure in a rat pharmacokinetic model. (C) 2009 Elsevier Ltd. All rights reserved.
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